PROJECT SUMMARY Pain management poses significant clinical challenges due to very high prevalence, diversity of underlying causes, and often a lack of safe and effective treatment options. Approximately 50 million Americans undergo inpatient surgical procedures every year and experience acute post-operative pain. An estimated 100 million US adults suffer from chronic pain conditions. Opioids are the most effective class of analgesics for moderate to severe pain and act primarily at mu opioid receptors (MOR). Unfortunately MOR activation is also associated with significant side effects including constipation, mental clouding and drowsiness, respiratory depression, nausea, vomiting, itching, and risks of dependence and addiction. For lack of better options, the number of opioid prescriptions and dose per prescription has increased over the past two decades. This has led to a ?pain medication epidemic? characterized by unprecedented levels of addiction and deaths either from unintentional overdose of medically prescribed drugs or illicit use of medications. Peripherally-selective peptidic kappa opioid receptor (KOR) agonists are emerging as a new class of analgesics. We previously pioneered the development of peptidic KOR agonists. These efforts led to the discovery of FE 200665 (a.k.a. CR665), an all D-amino acid tetrapeptide with unprecedented KOR selectivity and peripherally restricted activity. Clinical trials with CR665, and a closely related analog CR845, have established that peptidic KOR agonists (i) produce analgesia, (ii) lack CNS side-effects, (iii) do not produce constipation, and (iv) reduce the need for mu opioid supplemental therapy in acute post-operative pain. This first generation peptidic KOR agonist is however short-acting, requiring multiple daily intravenous injections, thereby limiting clinical utility and commercial interest. We propose to combine the above clinically-validated peptidic KOR agonist modality with our proprietary and clinically-validated peptide half-life extension technology. This involves the conjugation of an active peptide to a non-targeting antibody carrier, to create long-acting KOR (LA-KOR) agonists suitable for once-weekly (QW) subcutaneous (SC) administration. The proposed SBIR Phase I program will assess the feasibility to design a LA-KOR agonist chemical series with suitable KOR potency, selectivity, analgesic activity and duration of action to warrant further development. IMPACT &